Out of sight, out of mind: When and how perceived vulnerability decreases foreseeability and responsibility for causing harm in the marketplace.

Numerous social categories are often seen as vulnerable to harm. In the context of firms causing harm to individuals, we seek to better explain when and why observers absolve firms of responsibility as opposed to holding them more accountable. We propose that when someone's identity is thought to make them vulnerable to harm, identity visibility (how observable the identity is) and frequency (how common the identity is) influence the perceived foreseeability of a harmful event and firm responsibility. Across five studies (total N = 2,101), we find that when visibility and frequency are low, perceptions of foreseeability decrease, in turn decreasing firm responsibility. We illustrate how visibility and frequency, and in turn foreseeability, can vary based on the characteristics of the individual being observed (e.g., the visibility or rarity of a health condition) or context (e.g., an otherwise visible identity may be invisible in an online service context). Foreseeability and firm responsibility increased when the harmed individual's rare health condition was reframed to communicate the firm's likelihood of interacting with any individual with the same health condition. Implications for consumer welfare, policy, and inclusivity are discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Safety and Tolerability of a Novel Anti-HER2 Antibody-Drug Conjugate (PF-06804103) in Patients with HER2-Expressing Solid Tumors: A Phase 1 Dose-Escalation Study.

PF-06804103 is an anti-HER2 antibody-drug conjugate with auristatin payload. We evaluated its safety, tolerability, and antitumor activity in patients with advanced/unresectable or metastatic breast and gastric cancers. This multicenter, open-label, first-in-human, phase 1 study (NCT03284723) comprised dose escalation (P1) and dose expansion (P2). In P1, adults with HER2+ breast or gastric cancer received PF-06804103 0.15-5.0 mg/kg intravenously once/21 days (Q3W); in P2, patients with HER2+ or HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer received 3.0 or 4.0 mg/kg Q3W. The primary endpoints were dose-limiting toxicities (DLT) and safety (P1), and objective response rate (ORR) assessed using RECIST v1.1 (P2). Ninety-three patients enrolled in P1 (n = 47: HER2+ gastric cancer = 22, HER2+ breast cancer = 25) and P2 [n = 46: HER2+ breast cancer = 19, hormone receptor (HR)+ HER2-low breast cancer = 27] received PF-06804103. Four patients (3.0- and 4.0-mg/kg groups, n = 2 each) had DLTs (mostly Grade 3). Safety and efficacy results showed a dose-response relationship. Adverse events (AE) leading to treatment discontinuation (44/93, 47.3%) included neuropathy (11/93, 11.8%), skin toxicity (9/93, 9.7%), myalgia (5/93, 5.4%), keratitis (3/93, 3.2%), and arthralgia (2/93, 2.2%). Two (2/79, 2.5%) patients (P1, 4.0- and 5.0-mg/kg groups, n = 1 each) achieved complete response; 21 (21/79, 26.6%) achieved partial response. In P2, ORR was higher in HER2+ compared with HR+ HER2-low breast cancer [3.0 mg/kg: 16.7% (2/12) vs. 10.0% (1/10); 4.0 mg/kg: 47.4% (9/19) vs. 27.3% (3/11)]. PF-06804103 demonstrated antitumor activity; however, AEs led to discontinuation in 47.3% of patients. Safety and efficacy were dose-dependent.

Heroization and ironic funneling effects.

In recent years, much of the American public has venerated military veterans as heroes. Despite overwhelmingly positive public attitudes toward veterans, veterans have experienced higher rates of unemployment and underemployment than their nonveteran peers. The current research leverages theory and research on positive stereotypes to shed light on this seeming inconsistency between the heroization of veterans and their heightened rates of unemployment and underemployment. We conceptualize the hero label as a pervasive positive stereotype, and we employ complementary methods and designs (correlational, quasi-experimental, experimental, and mediational) to investigate the consequences and implications of attaching this label to military veterans. We then extend our theorizing to other heroized groups (e.g., firefighters, paramedics, teachers, and social workers). The results across studies suggest that heroization leads the American public to funnel heroized individuals and groups into a limited set of lower paying jobs, organizations, and careers associated with selflessness. This research not only offers insights into an important real-world problem but also offers a first experimental investigation of the consequences and implications of labeling a group of people as heroes. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Pixelwise H-score: A novel digital image analysis-based metric to quantify membrane biomarker expression from immunohistochemistry images.

Immunohistochemistry (IHC) assays play a central role in evaluating biomarker expression in tissue sections for diagnostic and research applications. Manual scoring of IHC images, which is the current standard of practice, is known to have several shortcomings in terms of reproducibility and scalability to large scale studies. Here, by using a digital image analysis-based approach, we introduce a new metric called the pixelwise H-score (pix H-score) that quantifies biomarker expression from whole-slide scanned IHC images. The pix H-score is an unsupervised algorithm that only requires the specification of intensity thresholds for the biomarker and the nuclear-counterstain channels. We present the detailed implementation of the pix H-score in two different whole-slide image analysis software packages Visiopharm and HALO. We consider three biomarkers P-cadherin, PD-L1, and 5T4, and show how the pix H-score exhibits tight concordance to multiple orthogonal measurements of biomarker abundance such as the biomarker mRNA transcript and the pathologist H-score. We also compare the pix H-score to existing automated image analysis algorithms and demonstrate that the pix H-score provides either comparable or significantly better performance over these methodologies. We also present results of an empirical resampling approach to assess the performance of the pix H-score in estimating biomarker abundance from select regions within the tumor tissue relative to the whole tumor resection. We anticipate that the new metric will be broadly applicable to quantify biomarker expression from a wide variety of IHC images. Moreover, these results underscore the benefit of digital image analysis-based approaches which offer an objective, reproducible, and highly scalable strategy to quantitatively analyze IHC images.

NOTCH3-targeted antibody drug conjugates regress tumors by inducing apoptosis in receptor cells and through transendocytosis into ligand cells.

Aberrant NOTCH3 signaling and overexpression is oncogenic, associated with cancer stem cells and drug resistance, yet therapeutic targeting remains elusive. Here, we develop NOTCH3-targeted antibody drug conjugates (NOTCH3-ADCs) by bioconjugation of an auristatin microtubule inhibitor through a protease cleavable linker to two antibodies with differential abilities to inhibit signaling. The signaling inhibitory antibody rapidly induces ligand-independent receptor clustering and internalization through both caveolin and clathrin-mediated pathways. The non-inhibitory antibody also efficiently endocytoses via clathrin without inducing receptor clustering but with slower lysosomal co-localization kinetics. In addition, DLL4 ligand binding to the NOTCH3 receptor mediates transendocytosis of NOTCH3-ADCs into ligand-expressing cells. NOTCH3-ADCs internalize into receptor and ligand cells independent of signaling and induce cell death in both cell types representing an atypical mechanism of ADC cytotoxicity. Treatment of xenografts with NOTCH3-ADCs leads to sustained tumor regressions, outperforms standard-of-care chemotherapy, and allows targeting of tumors that overexpress NOTCH3 independent of signaling inhibition.

The Challenges of Military Veterans in Their Transition to the Workplace: A Call for Integrating Basic and Applied Psychological Science.

Long-standing structural features of the military have created a culture and society that is dramatically different and disconnected from civilian society. Thus, veterans transitioning to civilian society face a number of challenges related to fulfilling basic psychological needs (e.g., need for structure and order, belonging) and civilians' reliance on stereotypes to understand military veterans. In an attempt to enrich the understanding of these challenges, we integrate social psychological theories and insights with research from sociology, clinical psychology, military psychology, and organizational behavior. Theories of compensatory control, stereotype threat, and stereotyping are drawn on to help explain the psychological challenges that veterans may encounter during their transition to civilian society. We present recent research that leverages these theories to understand issues veterans face. This theoretical integration illustrates the opportunity and potential for psychological researchers to conduct basic and applied research in the context of veterans and for clinicians and managers to draw on basic theory to inform programs and interventions.

Comparisons of patellar bone mineral density between individuals with and without patellofemoral pain.

BACKGROUND: Although bone stress injuries have been reported in individuals with patellofemoral pain (PFP), especially within the lateral patella, it remains unclear whether persons with PFP exhibit altered patellar regional bone mineral density (BMD). The primary purpose of this study was to compare BMD of the patella (lateral, medial, and total regions) between individuals with and without PFP using quantitative computed tomography (QCT). The secondary aim was to examine the associations between patellar regional BMD and patellofemoral joint (PFJ) alignment. METHODS: Ten individuals with retropatellar pain and 10 sex, age, weight, height, and activity matched pain-free controls underwent a QCT scan to obtain patellar BMD. To quantify PFJ alignment, patellar lateral displacement was measured using bisect-offset (BSO) index and patellar mediolateral tilt was quantified using patellar tilt angle (PTA). A two-factor repeated-measures ANOVA was used to compare BMD across the three patellar regions and between the two groups. Pearson correlation coefficient analyses were used to evaluate the associations between BMD and PFJ alignment of all participants. RESULTS: There was no difference in BMD between the two groups. However, BMD was highest within the lateral patella and was lowest within the medial patella across both groups. There were significantly moderate to large correlations between BSO index/PTA and BMD within lateral, medial, and total regions. CONCLUSIONS: While individuals with PFP and pain-free controls have similar patellar BMD, the lateral patella exhibits the highest BMD. Additionally, higher patellar regional BMD is related to increased patellar lateral displacement and lateral tilt.

Understanding contemporary forms of exploitation: Attributions of passion serve to legitimize the poor treatment of workers.

The pursuit of passion in one's work is touted in contemporary discourse. Although passion may indeed be beneficial in many ways, we suggest that the modern cultural emphasis may also serve to facilitate the legitimization of unfair and demeaning management practices-a phenomenon we term the legitimization of passion exploitation. Across 7 studies and a meta-analysis, we show that people do in fact deem poor worker treatment (e.g., asking employees to do demeaning tasks that are irrelevant to their job description, asking employees to work extra hours without pay) as more legitimate when workers are presumed to be "passionate" about their work. Of importance, we demonstrate 2 mediating mechanisms by which this process of legitimization occurs: (a) assumptions that passionate workers would have volunteered for this work if given the chance (Studies 1, 3, 5, 6, and 8), and (b) beliefs that, for passionate workers, work itself is its own reward (Studies 3, 4, 5, 6, and 8). We also find support for the reverse direction of the legitimization process, in which people attribute passion to an exploited (vs. nonexploited) worker (Study 7). Finally, and consistent with the notion that this process is connected to justice motives, a test of moderated mediation shows this is most pronounced for participants high in belief in a just world (Study 8). Taken together, these studies suggest that although passion may seem like a positive attribute to assume in others, it can also license poor and exploitative worker treatment. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

A phase I, dose-escalation study of PF-06650808, an anti-Notch3 antibody-drug conjugate, in patients with breast cancer and other advanced solid tumors.

Background PF-06650808 is a novel anti-Notch3 antibody-drug conjugate (ADC) able to deliver an auristatin-based cytotoxic payload to target cells. In this first-in-human, dose-finding, phase I study (NCT02129205), we investigated safety, pharmacokinetics, immunogenicity, and preliminary antitumor activity of single-agent PF-06650808 in 40 patients with advanced breast cancer (BC) and other solid tumors unselected for Notch3 expression. Primary endpoint was dose-limiting toxicity (DLT). PF-06650808 was administered intravenously every 3 weeks at a starting dose of 0.2 mg/kg, escalated up to 6.4 mg/kg following the modified continual reassessment method. An additional dose level, 2.0 mg/kg, was evaluated in patients with advanced, estrogen receptor-positive (ER+) BC. Results The majority of patients had advanced BC (60%) and almost all (90%) had received ≥3 prior lines of anticancer therapy. Treatment with PF-06650808 was generally well tolerated at dose levels ≤2.0 mg/kg with no DLTs. The maximum tolerated dose (MTD) was estimated to be 2.4 mg/kg. The most common treatment-related AEs in all patients were fatigue (40.0%), decreased appetite (37.5%), nausea (35.0%), alopecia (32.5%), abdominal pain (25.0%), pruritus (25.0%), and vomiting (25.0%). Five patients achieved a partial response (PR), including 2 unconfirmed PRs; 4 of the responders had ER+/PR+/HER2- BC. Sixteen (51.6%) patients achieved stable disease, including 8 (57.1%) of 14 patients with ER+ BC. Tumor samples from all responders tested positive for NOTCH3 expression in a retrospective, exploratory analysis. Conclusions The anti-Notch3 ADC PF-06650808 has demonstrated a manageable safety profile and early signs of antitumor activity in patients with advanced BC.

First-in-human, phase I study of PF-06647263, an anti-EFNA4 calicheamicin antibody-drug conjugate, in patients with advanced solid tumors.

PF-06647263, a novel antibody-drug conjugate consisting of an anti-EFNA4 antibody linked to a calicheamicin payload, has shown potent antitumor activity in human xenograft tumor models, including triple-negative breast cancer (TNBC). In the dose-escalation part 1 of this multicenter, open-label, phase I study (NCT02078752), successive cohorts of patients (n, 48) with advanced solid tumors and no available standard therapy received PF-06647263 every 3 weeks (Q3W) or every week (QW), following a modified toxicity probability interval (mTPI) method (initial dosing: 0.015 mg/kg Q3W). Primary objective in part 1 was to estimate the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D). In part 2 (dose-expansion cohort), 12 patients with pretreated, metastatic TNBC received PF-06647263 at the RP2D to further evaluate tumor response and overall safety. PF-06647263 QW administration (n, 23) was better tolerated than the Q3W regimen (n, 25) with only 1 DLT reported (thrombocytopenia). The most common AEs with the QW regimen (fatigue, nausea, vomiting, mucosal inflammation, thrombocytopenia, and diarrhea) were mostly mild to moderate in severity. The MTD was not estimated. PF-06647263 exposures increased in a dose-related manner across the doses evaluated. The RP2D was determined to be 0.015 mg/kg QW. Six (10%) patients achieved a confirmed partial response and 22 (36.7%) patients had stable disease. No correlations were observed between tumor responses and EFNA4 expression levels. Study findings showed manageable safety and favorable PK for PF-06647263 administered QW at the RP2D, with preliminary evidence of limited antitumor activity in patients with TNBC and ovarian cancer.

System justification: Experimental evidence, its contextual nature, and implications for social change.

We review conceptual and empirical contributions to system justification theory over the last fifteen years, emphasizing the importance of an experimental approach and consideration of context. First, we review the indirect evidence of the system justification motive via complimentary stereotyping. Second, we describe injunctification as direct evidence of a tendency to view the extant status quo (the way things are) as the way things should be. Third, we elaborate on system justification's contextual nature and the circumstances, such as threat, dependence, inescapability, and system confidence, which are likely to elicit defensive bolstering of the status quo and motivated ignorance of critical social issues. Fourth, we describe how system justification theory can increase our understanding of both resistance to and acceptance of social change, as a change moves from proposed, to imminent, to established. Finally, we discuss how threatened systems shore up their authority by co-opting legitimacy from other sources, such as governments that draw on religious concepts, and the role of institutional-level factors in perpetuating the status quo.

Detecting expression of 5T4 in CTCs and tumor samples from NSCLC patients.

The fetal oncogene 5T4 is a cell surface protein, with overexpression observed in a variety of cancers as compared to normal adult tissue. The ability to select patients with tumors that express high levels of 5T4 may enrich a clinical trial cohort with patients most likely to respond to 5T4 targeted therapy. To that end, we developed assays to measure 5T4 in both tumors and in circulating tumor cells (CTCs). We identified the presence of 5T4 in both adenocarcinoma and squamous cell carcinoma of lung, in all clinical stages and grades of disease. CTCs were identified in peripheral blood from the majority of patients with NSCLC, and 5T4 was detectable in most samples. Although 5T4 was present in both CTCs and tumors in most patients, there was no concordance between relative amount in either sample type. Clinical response rates of patients treated with the therapies directed against 5T4 in early stage clinical trials, as determined by these assays, may provide important insights into the biology of 5T4 in tumors and the mechanisms of action of 5T4-targeting therapy.

Efficacy of Cotargeting Angiopoietin-2 and the VEGF Pathway in the Adjuvant Postsurgical Setting for Early Breast, Colorectal, and Renal Cancers.

Antiangiogenic tyrosine kinase inhibitors (TKI) that target VEGF receptor-2 (VEGFR2) have not been effective as adjuvant treatments for micrometastatic disease in phase III clinical trials. Angiopoietin-2 (Ang2) is a proangiogenic and proinflammatory vascular destabilizer that cooperates with VEGF. The purpose of this study was to test whether CVX-060 (an Ang2-specific CovX-body) can be combined with VEGFR2-targeting TKIs (sunitinib or regorafenib) to successfully treat postsurgical metastatic disease in multiple orthotopically implanted human tumor xenograft and syngeneic murine tumor models. In the MDA-MB-231.LM2-4 human breast cancer model, adjuvant sunitinib was ineffective, whereas adjuvant CVX-060 delayed the progression of pulmonary or distant lymphatic metastases; however, overall survival was only improved with the adjuvant use of a VEGF-A/Ang2-bispecific CovX-body (CVX-241) but not when CVX-060 is combined with sunitinib. Adjuvant CVX-241 also showed promise in the EMT-6/CDDP murine breast cancer model, with or without an immune checkpoint inhibitor (anti-PD-L1). In the RENCA model of mouse renal cancer, however, combining CVX-060 with sunitinib in the adjuvant setting was superior to CVX-241 as treatment for postsurgical lung metastases. In the HCT116 and HT29 xenograft models of colorectal cancer, both CVX-060 and regorafenib inhibited liver metastases. Overall, our preclinical findings suggest differential strategies by which Ang2 blockers can be successfully combined with VEGF pathway targeting in the adjuvant setting to treat micrometastatic disease-particularly, in combination with VEGF-A blockers (but not VEGFR2 TKIs) in resected breast cancer; in combination with VEGFR2 TKIs in resected kidney cancer; and as single agents or with VEGFR2 TKIs in resected colorectal cancer. Cancer Res; 76(23); 6988-7000. ©2016 AACR.

Chemoenzymatic synthesis of enantiopure hydroxy sulfoxides derived from substituted arenes.

Enantiopure ß-hydroxy sulfoxides and catechol sulfoxides were obtained, by chemoenzymatic synthesis, involving dioxygenase-catalysed benzylic hydroxylation or arene cis-dihydroxylation and cis-diol dehydrogenase-catalysed dehydrogenation. Absolute configurations of chiral hydroxy sulfoxides were determined by X-ray crystallography, ECD spectroscopy and stereochemical correlation. The application of a new range of ß-hydroxy sulfoxides as chiral ligands was examined.

Predictive markers of efficacy for an angiopoietin-2 targeting therapeutic in xenograft models.

The clinical efficacy of anti-angiogenic therapies has been difficult to predict, and biomarkers that can predict responsiveness are sorely needed in this era of personalized medicine. CVX-060 is an angiopoietin-2 (Ang2) targeting therapeutic, consisting of two peptides that bind Ang2 with high affinity and specificity, covalently fused to a scaffold antibody. In order to optimize the use of this compound in the clinic the construction of a predictive model is described, based on the efficacy of CVX-060 in 13 cell line and 2 patient-derived xenograft models. Pretreatment size tumors from each of the models were profiled for the levels of 27 protein markers of angiogenesis, SNP haplotype in 5 angiogenesis genes, and somatic mutation status for 11 genes implicated in tumor growth and/or vascularization. CVX-060 efficacy was determined as tumor growth inhibition (TGI%) at termination of each study. A predictive statistical model was constructed based on the correlation of these efficacy data with the marker profiles, and the model was subsequently tested by prospective analysis in 11 additional models. The results reveal a range of CVX-060 efficacy in xenograft models of diverse tissue types (0-64% TGI, median = 27%) and define a subset of 3 proteins (Ang1, EGF, Emmprin), the levels of which may be predictive of TGI by Ang2 blockade. The direction of the associations is such that better efficacy correlates with high levels of target and low levels of compensatory/antagonizing molecules. This effort has revealed a set of candidate predictive markers for CVX-060 efficacy that will be further evaluated in ongoing clinical trials.

The Effect of Molecular Weight, PK, and Valency on Tumor Biodistribution and Efficacy of Antibody-Based Drugs.

Poor drug delivery and penetration of antibody-mediated therapies pose significant obstacles to effective treatment of solid tumors. This study explored the role of pharmacokinetics, valency, and molecular weight in maximizing drug delivery. Biodistribution of a fibroblast growth factor receptor 4 (FGFR4) targeting CovX-body (an FGFR4-binding peptide covalently linked to a nontargeting IgG scaffold; 150 kDa) and enzymatically generated FGFR4 targeting F(ab)2 (100 kDa) and Fab (50 kDa) fragments was measured. Peak tumor levels were achieved in 1 to 2 hours for Fab and F(ab)2 versus 8 hours for IgG, and the percentage injected dose in tumors was 0.45%, 0.5%, and 2.5%, respectively, compared to 0.3%, 2%, and 6% of their nontargeting controls. To explore the contribution of multivalent binding, homodimeric peptides were conjugated to the different sized scaffolds, creating FGFR4 targeting IgG and F(ab)2 with four peptides and Fab with two peptides. Increased valency resulted in an increase in cell surface binding of the bivalent constructs. There was an inverse relationship between valency and intratumoral drug concentration, consistent with targeted consumption. Immunohistochemical analysis demonstrated increased size and increased cell binding decreased tumor penetration. The binding site barrier hypothesis suggests that limited tumor penetration, as a result of high-affinity binding, could result in decreased efficacy. In our studies, increased target binding translated into superior efficacy of the IgG instead, because of superior inhibition of FGFR4 proliferation pathways and dosing through the binding site barrier. Increasing valency is therefore an effective way to increase the efficacy of antibody-based drugs.

On the perpetuation of ignorance: system dependence, system justification, and the motivated avoidance of sociopolitical information.

How do people cope when they feel uninformed or unable to understand important social issues, such as the environment, energy concerns, or the economy? Do they seek out information, or do they simply ignore the threatening issue at hand? One would intuitively expect that a lack of knowledge would motivate an increased, unbiased search for information, thereby facilitating participation and engagement in these issues-especially when they are consequential, pressing, and self-relevant. However, there appears to be a discrepancy between the importance/self-relevance of social issues and people's willingness to engage with and learn about them. Leveraging the literature on system justification theory (Jost & Banaji, 1994), the authors hypothesized that, rather than motivating an increased search for information, a lack of knowledge about a specific sociopolitical issue will (a) foster feelings of dependence on the government, which will (b) increase system justification and government trust, which will (c) increase desires to avoid learning about the relevant issue when information is negative or when information valence is unknown. In other words, the authors suggest that ignorance-as a function of the system justifying tendencies it may activate-may, ironically, breed more ignorance. In the contexts of energy, environmental, and economic issues, the authors present 5 studies that (a) provide evidence for this specific psychological chain (i.e., ignorance about an issue → dependence → government trust → avoidance of information about that issue); (b) shed light on the role of threat and motivation in driving the second and third links in this chain; and (c) illustrate the unfortunate consequences of this process for individual action in those contexts that may need it most.